Outcomes of Secondary Hyperparathyroidism in Chronic Kidney Disease and the Direct Costs of Treatment

BACKGROUND: There has been an emphasis over the last several years to identify and treat chronic kidney disease (CKD) and its complications as they evolve rather than waiting until the patient reaches end-stage renal disease (ESRD), also known as CKD stage 5. The number of patients who will be identified and prescribed therapies for complications such as secondary hyperparathyroidism (SHPT) is greater than initially proposed. OBJECTIVES: To review the pathways, complications, management, and estimated treatment costs of CKD-related SHPT. METHODS: An electronic literature search of MEDLINE (January 1980 through January 2007) was conducted for English-language publications using the base search term secondary hyperparathyroidism. To refine subsequent searches, the authors added Boolean operators to the following secondary and tertiary search terms: parathyroid hormone, chronic kidney disease, renal osteodystrophy, adynamic bone disease, vascular calcification, cardiovascular disease, vitamin D, vitamin D analogs, hypercalcemia, hyperphosphatemia, calcimimetics, costs, prevalence, and economics. RESULTS: The initial MEDLINE search produced 278 relevant articles. After refining the search terms, the authors triaged the results for English-language publications relevant to the discussion of SHPT and its complications in CKD, eliminating 149 publications. The remaining 129 publications were accepted for review. These articles represent a growing body of primarily observational evidence that demonstrates that elevated intact parathyroid hormone (PTH) levels cause deleterious physiological results across a variety of organ systems, including the cardiovascular and skeletal systems. Specific complications associated with SHPT are left ventricular hypertrophy (LVH), renal osteodystrophy (ROD), and extraskeletal calcification. Medical management of the PTH/vitamin D/calcium and phosphorus imbalances in SHPT focus on regulating PTH levels via vitamin D therapy. The class of calcimimetics is a newer treatment modality that has favorable effects on biochemical laboratory values, such as serum calcium and phosphorus levels, but current data do not show differences on hard endpoint patient-oriented outcomes compared with standard generic agents. The direct drug costs in April 2007 U.S. dollars of treating CKD-associated elevations in PTH in predialysis patients range from $8.40 per patient per week ($437 per year) for oral generic calcitriol to $88.90 per patient per week ($4,623 per year) for oral paricalcitol (expressed as 85% of average wholesale price [AWP] for brand drugs or 70% of AWP for generic drugs). The direct drug costs of treating SHPT in hemodialysis patients range from $80.20 per patient per week ($4,170 per year) for generic calcitriol (IV) to $278.46 per patient per week ($14,480 per year) for oral cinacalcet. CONCLUSIONS: SHPT causes skeletal and cardiovascular complications in CKD patients. Calcitriol therapy is effective in managing PTH levels, but efforts to reduce the associated hypercalcemia and hyperphosphatemia have led to the development of newer, yet more expensive, vitamin D analogs. With the lack of evidence to support comparative superior outcomes in end-organ disease among SHPT therapy alternatives, future research is still needed to clearly identify which newer agents are most competitive with the historical gold standard of calcitriol therapy.

including renal osteodystrophy (ROD), extraskeletal calcification, and cardiovascular disease (CVD), resulting in increased mortality. 7 These complications associated with CKD result in elevated rates of hospitalization and increased health care expenditures. In a retrospective cohort study group of 109,321 elderly patients, Mix et al. found that hospitalization rates increased markedly with the progression of CKD, peaking at 487 hospitalizations/1,000 patient months at risk after initiation of dialysis. 8 The majority of these hospitalizations, both before and after dialysis, were due to CKD comorbidities, particularly CVD diagnoses and events. Moreover, the economic burden of CKD and its complications is staggering. The cost to treat CVD, infections, and related hospitalizations associated with CKD is estimated at $90 billion, 9 and treating CKD is projected to cost the Medicare system more than $28 billion in 2010, an increase from $12 billion in 1998. 10 Several treatment options are available to slow the progression of CKD. A component of CKD care often overlooked and undertreated by both the primary care physician and the nephrologist is the management of SHPT, which can lead to CVD and ROD if untreated. Since kidney disease is often diagnosed comparatively late in many patients, the staging at diagnosis is often stage 3 or 4, the same time that these extrarenal complications begin to appear. [11][12][13][14] Thus, many patients who acquire the CKD diagnosis often have had chronic exposure to reductions in vitamin D and serum calcium, and elevations in PTH and phosphorus, and may manifest significant skeletal and/or cardiovascular sequelae.
This review focuses on the complications of elevated parathyroid hormone level and their prevalence, evaluates current avenues of treatment, and introduces the subject of the economic impact of different treatments.

■■ Parathyroid Hormone Regulation
The parathyroid glands are responsible for maintaining calcium homeostasis through the actions of PTH, a polypeptide hormone. Fluctuations in serum calcium concentration are detected by calcium receptors (CaRs)-G-protein-coupled receptors located on the chief cells of the parathyroid gland that mediate the secretion of PTH. 15 Stimulated by low serum calcium levels, PTH secretion increases and up-regulates the expression of 1α-hydroxylase in the kidney. This enzyme is responsible for the production of vitamin D (1,25-dihydroxyvitamin D 3 or calcitriol). 16 Under hypocalcemic conditions, PTH stimulates the synthesis of calcitriol, correcting the calcium imbalance by (1) increasing absorption of calcium from the gastrointestinal tract, (2) conserving calcium that would ordinarily be excreted by the kidneys, and (3) releasing calcium from bone (see Figure). 17 It has been suggested that PTH levels and the serum phosphorus equilibrium are also linked. Patients with advanced CKD who were administered a low-phosphorus diet showed reductions in serum PTH levels independent of calcium and calcitriol concentrations. 18 Recent studies have elaborated on the role of phosphorus in PTH regulation. Animal models have shown that dietary phosphorus can alter PTH mRNA expression and, moreover, phosphorus has been shown to directly stimulate PTH secretion from parathyroid cells. [19][20][21] Calcitriol and PTH are both capable of directly regulating serum mineral levels, as shown in the Figure. The effects of PTH on the intestine are accomplished indirectly through the actions of calcitriol. Acting to increase calcium absorption, calcitriol has been shown to up-regulate the expression of calcium channel and transporter proteins, correcting hypocalcemia at the transcriptional level. 22 The effects of elevated PTH levels on the skeleton include the stimulation of calcium mobilization from bone and the direct  regulation of osteoblast apoptosis to correct hypocalcemia. 23 Completing the feedback loop, both elevated calcium and calcitriol levels can suppress PTH secretion but via different mechanisms. Sela-Brown et al. have shown that calcitriol suppresses PTH synthesis at the transcriptional level whereas calcium regulation is posttranscriptional. 24 Abnormalities in mineral homeostasis usually originate from the failure to maintain this critical feedback loop, often leading to hyperparathyroidism.

■■ Secondary Hyperparathyroidism
SHPT is a major complication of CKD, resulting from disturbances in the regulation of PTH, calcium, phosphorus, and vitamin D (see Figure). Although hyperphosphatemia appears to be particularly important in the development of SHPT, the complication often occurs early in stage 3 of kidney failure, before the development of hyperphosphatemia. 25,26 A majority, if not all, of untreated CKD patients will develop SHPT as a result of the kidney' s inability to maintain mineral homeostasis.
In patients with stage 2 CKD (GFR 60-89 mL/min), levels of vitamin D are often depressed in conjunction with rising serum PTH levels. 27,28 This decline in vitamin D level can be attributed to decreased expression of 1α-hydroxylase, the kidney-localized enzyme responsible for converting 25-hydroxyvitamin D 3 to biologically active vitamin D (1,25-dihydroxyvitamin D 3 ). 29 Alternatively, reduced 25-hydroxyvitamin D 3 concentrations have also been found in CKD patients, resulting in less substrate available for the 1α-hydroxylase. 30 34 A further consequence of SHPT arises through the growth of the nodular tissue that accompanies parathyroid gland hyperplasia. This nodular tissue has been shown to be less sensitive to elevated calcium levels, severing the calcium-level feedback loop. 35 The Dialysis Outcomes and Practice Patterns Survey, a large international observational study, found clinically unacceptable elevations in PTH (>300 pg/mL) in 25% of end-stage renal disease (ESRD) patients (range: 19%-31% for Japan and the United Kingdom, respectively). 36 Determining mean measures of SHPT prevalence are challenging, however, as risk has been shown to vary widely among patient populations. For example, African American CKD patients are more than twice as likely to develop SHPT as are white CKD patients. 37 This finding is thought to be due to the decreased synthesis of 25-dihydroxyvitamin D 3 in response to sunlight among African Americans, perhaps due to skin pigmentation. 38 In contrast, diabetic CKD patients have markedly lower PTH levels and a decreased risk of SHPT, perhaps due to PTH suppression by hyperglycemia. 38 Chronic SHPT is associated with several complications ( Table 2). Two major concerns for patients with SHPT are ROD and progressive CVD. 39,40 CVD is particularly important, accounting for more than 50% of all stage-5 CKD patient deaths. 41 A retrospective analysis of the United States Renal Data System Waves 1, 3, and 4 Study suggested that disorders of calcium homeostasis are often associated with higher incidences of fatal and nonfatal cardiovascular events and all-cause mortality in hemodialysis patients. 42 Despite the lack of a definitive link between PTH and increased CVD risk, there are observational data that illustrate a strong association between cardiac mortality and serum phosphate and calcium-phosphate (Ca x P) product levels. Hyperphosphatemia is often closely associated with SHPT in the context of increased mortality in dialysis patients. 43 The adjusted relative risk of death was found to be higher with serum phosphate levels greater than 6.5 mg/dL and Ca x P product levels greater than 72 mg 2 /dL 2 . This translates into a 1.27 and 1.34 relative mortality risk for elevated serum phosphorus and Ca x P product levels, respectively. 44 In addition to hyperphosphatemia and an elevated Ca x P product, other widespread observational findings in CKD patients are considered to be independent risk factors for CVD, including hypertension, left ventricular hypertrophy (LVH), increased serum creatinine levels, and microalbuminuria. 45 Traditional risk factors such as smoking, diabetes, hypertension, dyslipidemia, and obesity can be present at all stages of CKD and may also increase the risk of CVD. 46 The prominent role that ROD and CVD comorbidities play in the increased mortality and treatment cost of CKD warrant further discussion of these conditions.

Renal Osteodystrophy
The processes of bone absorption and resorption are closely regulated in healthy individuals. ROD arises as a consequence of bone remodeling dysregulation. While the pathogenesis of ESRD is similar across patients, the pathogenesis of ROD varies from high-to low-bone turnover. Elevated levels of PTH stimulate bone demineralization and lead to high-bone turnover, a condition characterized by accelerated rates of bone absorption and resorption. The new bone is structurally inferior and fragile, and carries an increased risk of fractures. 47 The classic histological form of ROD is osteitis fibrosa, which arises from increased bone Complications of Secondary Hyperparathyroidism. 7,51 remodeling and fibrosis of the marrow. 48,49 Presentation of reduced bone mass, increased nonlamellar bone via biopsy, osteopenia, and fractures accompany osteitis fibrosa. 50 Conversely, depressed PTH levels as a consequence of parathyroidectomy or overtreatment with vitamin D can lead to low-bone turnover disease, characterized by lower rates of bone absorption and resorption. Osteomalacia arises through decreased remodeling coupled to a mineralization defect causing accumulation of unmineralized osteoid. 51 Adynamic bone disease is another manifestation of low-bone turnover ROD, characterized by reduced bone volume, mineralization, and collagen synthesis due, in part, to decreased cellular activity . 52 As this generalized dormancy leads to fewer active bone remodeling sites, adynamic bone disease is associated with a decreased ability of the skeleton to buffer serum calcium fluctuations. 51 As shown in Table 3, prevalence of high-versus low-bone turnover ROD depends strongly on CKD staging. High-bone turnover dominates in CKD stages 3-4 with 90% of the ROD caseload as determined by bone biopsy. 53 In ESRD patients, low-bone turnover disease becomes increasingly prevalent, due, in part, to PTH oversuppression, aluminum intoxication, and high calcium dialysate concentrations. 51 Osteitis fibrosa represents 25% to 40% of ROD seen in ESRD patients, compared with 60% low-bone turnover. 54 Of that percentage, adynamic bone accounts for 20% to 40% of the low-bone turnover ROD, and osteomalacia, 4% to 12%, along with some mixed osteodystrophy histology .55,56

Cardiovascular Disease
The elevated risk of cardiovascular mortality in CKD patients is responsible, in part, for the steep decline in the numbers of latestage CKD patients. Studies show that more than 40% of all deaths in ESRD patients are linked to CVD and that CVD mortality is 10 to 70 times greater in the dialysis population than in the general age-matched cohort. 57 The soft-tissue and vascular calcification that accompanies SHPT in advanced CKD is associated with a high risk of cardiac events among dialysis patients.
LVH is the most prevalent cardiac complication observed in CKD patients and is often associated with myocardial fibrosis, poor perfusion, and cell death. [57][58][59][60][61] Increased cardiac afterload, a potential consequence of increased arterial resistance due to vascular calci-fication, induces formation of the pathophysiology. 61 In a crosssectional study, Saleh et al. found PTH to be an independent predictor of LVH among patients in the upper PTH percentiles (>3.3 pmol/L for men and >3.1 pmol/L for women). 62 Nasri et al. analyzed the influence of PTH on myocardial function. In their cross-sectional study in hemodialysis patients, they determined that excess PTH played a significant role in the development of LVH and reduced left ventricular ejection fraction. 63 In a decade-long retrospective study, Dai et al. found a 52% prevalence of severe LVH among ESRD patients. 64 Ha et al. further extended the links between LVH and CKD, finding an 87% prevalence of concentric and eccentric LVH among predialysis patients. 65 Foley et al. corroborated the results in a decade-long prospective study, finding that 80% of the 433 patients initiating dialysis presented with LVH on echocardiography. 66 The relationship between elevated PTH and LVH was further explored in a retrospective study by Goto et al., who determined that parathyroidectomy in CKD patients with advanced SHPT led to a significant improvement of left ventricular ejection fraction and function. 67 A prospective study of 15 patients by Park et al. confirmed the association with SHPT, finding that PTH-suppressive calcitriol therapy led to a regression in myocardial hypertrophy in dialysis patients. 68 Hyperphosphatemia and hypercalcemia have been shown to promote calcification of the vasculature, myocardium, and cardiac valves. [69][70][71] Vascular calcification, manifested in reduced vessel wall elasticity, increased intima-media layer thickness and enhanced pulse-wave velocity, has been linked to LVH, and occurs with increased severity in dialysis patients versus non-CKD patients. 72 One observational study demonstrated as many as 92% of young adult dialysis patients had evidence of coronary arterial calcifications. 73 Furthermore, vascular and soft-tissue calcifications are strong predicators of cardiovascular mortality among CKD patients. 40,74 Retrospective studies by Block et al. and Ganesh et al. suggest that hyperphosphatemia (>6.5 mg/dL) and increased Ca x P product (>72 mg 2 /dL 2 ) are factors that contribute to the high mortality rate in dialysis patients. 44,75,76 Peripheral artery disease (PAD) has recently surfaced as a CKDrelated disorder. Manifested commonly as claudication, resting pain, or numbness of the lower extremities, PAD is a consequence of the atherosclerosis of the arteries that serve those regions. One observational study demonstrated a high prevalence of PAD in nondialyzed CKD patients upon first-time referral to a nephrology clinic. A higher prevalence was also seen in those patients with a greater severity of SHPT (PTH 228 ± 267 pg/mL). 77 Shane et al. postulated that SHPT might be a contributing factor in congestive heart failure (CHF). The authors analyzed 101 patients (79 men and 22 women, aged 25 to 70 years) with severe CHF who were referred for evaluation for cardiac transplantation. Osteoporosis and osteopenia were observed in approximately half these patients, as well as SHPT (30%) and vitamin D deficiency (26%). 78

Current Treatment Options for Secondary Hyperparathyroidism
In recent years, clinical research has demonstrated that along with PTH regulation, controlling mineral homeostasis (calcium, phosphorus, and Ca x P product) may reduce morbidity and mortality in patients with SHPT. 79 While oral phosphate-binding agents (calcium, sevelamer, lanthanum, magnesium, and aluminum) are used to reduce blood concentrations of phosphorus and are often taken concurrently with vitamin D (when SHPT is present), the focus of this article is on SHPT and its treatments. Vitamin D therapy is the standard medical treatment for predialysis and ESRD patients with vitamin D deficiency due to progressive kidney failure and associated elevations in PTH levels that exceed the K/DOQI-targeted ranges for the CKD stage. 80 Calcimimetic therapy is also approved for SHPT treatment in ESRD patients. The overall goal of treatment is to restore the PTH-calcium-vitamin D endocrine feedback loop, reestablish mineral homeostasis, and reduce the associated complications. 81 Important clinical trial data that report efficacy and safety for SHPT therapies are compiled in Table 4. Costs associated with current pharmacological treatments of SHPT in CKD are reported in Table 5.

Ergocalciferol
Ergocalciferol (Drisdol and generics, vitamin D 2 ), available as an oral capsule, is indicated for use in CKD stages 3-4 patients with vitamin D deficiency and concomitant elevation in PTH. It is U.S. Food and Drug Administration (FDA)-approved for the treatment of vitamin D deficiency, etiology unspecified. A prohormone, ergocalciferol, must be activated in the liver and kidney to biologically active forms of vitamin D 2 . 82 While recommended by the K/DOQI guidelines for treating 25-hydroxyvitamin D deficiency, ergocalciferol' s effectiveness in PTH inhibition is not well defined. 83,84 Calcitriol Calcitriol (Rocaltrol, Calcijex, and generic 1,25 dihydroxyvitamin D 3 ) is available as an oral solution, oral capsule, and injectable formulation. The oral formulations are approved in CKD stages 3-5 patients for the treatment of SHPT and in dialysis patients for the treatment of hypocalcemia and metabolic bone disease. The intravenous formulation is approved for the treatment of hypocalcemia and SHPT in hemodialysis patients. Administration of biologically active vitamin D (calcitriol) has been shown effective in treating the underlying deficiency in SHPT. In fact, the use of either oral or intravenous calcitriol has been shown to inhibit PTH synthesis and secretion and prevent parathyroid gland hyperplasia in CKD patients. 85 Furthermore, calcitriol has been approved for the pediatric dialysis population. However, calcitriol efficacy is limited by the development of hypercalcemia and the aggravation of hyperphosphatemia prevalent in CKD patients. 86 Both conditions have been linked to visceral and vascular calcification; furthermore, calcium loading has been associated with bone loss in dialysis patients. 87 A detailed under-standing of calcitriol and vitamin D receptor interactions has led to the development of 3 generations of vitamin D analogs that attenuate PTH levels with fewer adverse mineral homeostatic effects. Two vitamin D analogs approved for use in the United States are doxercalciferol (Hectorol) and paricalcitol (Zemplar).

Doxercalciferol
Doxercalciferol (Hectorol, 1α-hydroxyvitamin D 2 ) is a secondgeneration prohormone analog, biologically activated in the liver mainly to 1,25-dihydroxyvitamin D 2 . 88 Doxercalciferol has been approved for use in CKD stages 3-5, including dialysis, and is administered as an oral capsule for CKD stages 3-4 and as an intravenous solution for dialysis patients. 88 In a recent double-blinded, multicenter randomized controlled trial (RCT) of 55 predialysis patients, Coburn et al. found that, at study' s end, 74% of patients showed a ≥30% reduction in PTH levels and that 56% of patients had met their K/DOQI PTH target. 89 Evaluating doxercalciferol in dialysis patients in a open-label study, Maung et al. found that 95% of patients (94% and 95%, intravenous and oral doxercalciferol formulations, respectively) had ≥30% reductions in PTH levels, and 77% of patients on the oral doxercalciferol regimen achieved their K/DOQI recommendations for PTH control. 90 While PTH suppressive in the adult CKD population, doxercalciferol awaits prospective study and FDA approval in the pediatric CKD population.
Although less calcemic and phosphatemic than calcitriol, preclinical studies raised concern over the calcemic and phosphatemic potential of doxercalciferol. 91,92 Despite clinically important PTH suppression, Tan et al. found doxercalciferol therapy unacceptably raised serum mineral levels by 13 times in half the ESRD patients in the observational study, totaling 4.9 hypercalcemic episodes and 10.1 hyperphosphatemic episodes per 100 weeks of treatment. 93 In a double-blind RCT investigating doxercalciferol therapy in dialysis patients suffering from moderate-to-severe SHPT, Frazao et al. found that 82 of the 99 patients (83%) studied achieved PTH targets but with concomitant mild hypercalcemia and hyperphosphatemia. 94 A crossover study comparing doxercalciferol and paricalcitol found equipotent PTH suppression but a higher incidence of hyperphosphatemia among doxercalciferol recipients, twice that seen with paricalcitol therapy. 95 A paucity of comparative data exists between doxercalciferol versus calcitriol, highlighting the need for future prospective study.

Paricalcitol
Paricalcitol (Zemplar, 19-nor-1,25-dihydroxyvitamin D 2 ) is a thirdgeneration vitamin D analog that is bioactive upon administration, mimicking the actions of calcitriol on the vitamin D receptor. 82 Similarly to doxercalciferol, paricalcitol has been approved for CKD stages 3-5, administered as an oral capsule for predialysis patients and intravenously in dialysis patients. 96 Paricalcitol was proven safe and effective versus placebo in both short-term and long-term studies. Double-blind RCTs in predialysis patients demonstrated the clinical efficacy of oral paricalcitol, finding 91% of patients reached the primary endpoint of 2 consecutive reductions of ≥30% in PTH levels. 97   Adverse events that were considered by the investigator to have a possible relationship to the study drug occurred in 26% of patients, namely nausea/vomiting and metallic taste.

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Comparing paricalcitol with calcitriol in a head-to-head, multicenter RCT in dialysis patients, Sprague et al. found that paricalcitoltreated patients reached a ≥50% reduction in baseline PTH significantly faster than did calcitriol patients (87 days vs. 107 days, respectively). 100  Vomiting (not quantified) occurred more often in cinacalcet patients than in placebo patients.

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Summary of Literature for SHPT Therapy (continued) The efficacy of paricalcitol was extended successfully to difficult-to-treat hyperphosphatemic patients in an open-label study. 99 Lindberg et al. showed that among 35 initially hyperphosphatemic patients (mean phosphorus levels 8.0 mg/dL), phosphorus levels fell with a mean decrease of 0.57 ± 0.52 mg/dL. 99 Based on the results in adult patients, a placebo-controlled study was performed in pediatric and adolescent SHPT patients (aged 5-19 years), finding positive PTH suppression without concomitant elevations in serum calcium and phosphorus levels. 101 Paricalcitol was subsequently approved for the pediatric population and is the only vitamin D analog approved for these CKD patients.
Several comparative studies suggest clinical superiority of paricalcitol over calcitriol and doxercalciferol. A large 2-year retrospective study evaluating paricalcitol and calcitriol was undertaken by Mittman et al., demonstrating paricalcitol superiority in PTH suppression, mineral metabolism, and adverse events reduction. 102 Mean PTH levels were significantly higher for calcitriol in comparison with paricalcitol (247 pg/mL vs. 190 pg/mL) as was corrected calcium (9.71 ± 0.55 vs. 9.53 ± 0.67) and phosphorus levels (4.98 ± 0.93 vs. 4.79 ± 0.90). The majority (79%) of study participants were African American, a cohort with elevated risk of SHPT. 36 Comparing paricalcitol with doxercalciferol in a small crossover study, Martin et al. found doxercalciferol produced twice as many hyperphosphatemic episodes at similar levels of PTH suppression. 95 To better address the concerns of hypercalcemia and hyperphosphatemia, 2 prospective crossover studies were performed with dialysis patients. Patients were placed on low calcium and phosphorus diets and were randomly assigned to 1 of 2 drugs at the start of the study. After being administered a single high dose of the drug, serum calcium and phosphorus levels were measured. The protocol was subsequently repeated with the alternate drug. Comparing calcitriol and paricalcitol, Coyne    Outcomes of Secondary Hyperparathyroidism in Chronic Kidney Disease and the Direct Costs of Treatment mmol 2 /L 2 ) with paricalcitol therapy. 103 Joist et al. found paricalcitol and doxercalciferol showed equipotent PTH suppression but serum phosphorus levels rose significantly higher during doxercalciferol therapy (2.12 ± 0.11 mmol/L vs. 1.85 ± 0.07 mmol/L, doxercalciferol and paricalcitol, respectively). 104 Comparing mortality between calcitriol and paricalcitol recipients over a 3-year period, an uncontrolled historical cohort analyzed from the databases of the U.S.-based Fresenius Medical Care North America provided tantalizing findings when published in 2003. Teng et al. found dialysis patients receiving paricalcitol achieved a 16% survival advantage over calcitriol recipients that was apparent at 12 months. 105 The authors speculated the survival advantage seen with paricalcitol therapy was due to the nonclassical targets of paricalcitol. 105,106 However, this advantage of paricalcitol may be explained by considering small differences between the study groups; namely, a longer duration of dialysis before enrollment (90 days) and a higher population of African Americans in the paricalcitol arm (39% vs. 36%). Since African American dialysis patients are known to be at higher risk for SHPT and CVD, the observational data may only be showing that the greater the degree of hyperparathyroidism, the greater the benefit from paricalcitol treatment.
In a recent 2-year retrospective study, Kalantar-Zadeh et al. found that dialysis patients treated with paricalcitol demonstrated a survival benefit, up to a maximum 40% survival advantage. 107 Most recently, however, Tentori et al. studied mortality over a 5-year period in dialysis patients from a not-for-profit group, which overrepresented African American patients (44.5%). 108 In all models of mortality rate (deaths/100 patient-years), paricalcitol and doxercalciferol performed similarly (13.6-17.1 for doxercalciferol vs. 13.6-16.9 for paricalcitol). Although unadjusted results showed a survival advantage of both doxercalciferol and paricalcitol versus calcitriol, when models were adjusted for laboratory values and clinic standardized mortality, the hazard ratios for doxercalciferol and paricalcitol versus calcitriol both increased and were no longer statistically significant.

Molecular Mechanisms Differentiating Vitamin D-Based Therapies
The reduced calcemic and phosphatemic potential seen in paricalcitol versus calcitriol and doxercalciferol appears to be due, in part, to differences in intestinal absorption. 22 In a preclinical murine model, Slatopolsky et al. demonstrated that paricalcitol treatment causes reduced intestinal absorption of calcium and phosphorus versus equipotent doses of calcitriol. 109 The cause of this clinical advantage has been investigated on the molecular level and appears to be mediated by transcription of genes in enterocytes. Vitamin D compounds are believed to increase intestinal calcium absorption by up-regulating calcium-transporter-1 (CaT1) on the luminal membrane, calbindin in the cytosol, and plasma membrane calcium ATPase-1 (PMCA1) on the basolateral membrane of enterocytes. 22 Northern blot analysis in an experimental rat model revealed paricalcitol to be less potent than calcitriol in stimulating expression of CaT1, calbindin, and PMCA1. 22 The differentiation of vitamin D therapies regarding ROD was further studied in vitro, revealing more molecular-level evidence in support of clinical data. The stimulation of collagen synthesis, a marker of bone growth, was investigated in mouse calvariae culture as a function of vitamin D therapy. 110 Nakane et al. found paricalcitol more potent than either calcitriol or doxercalciferol in the increased expression of collagen. The rate of osteoclastic bone resorption was also investigated as a function of drug therapy in mouse calvariae culture. The same group found paricalcitol to be at least 10-fold less active in mobilizing skeletal calcium than either calcitriol or doxercalciferol. 110 A similar study found calcitriol-treated osteoclasts resorbed a 63% greater area than paricalcitol-treated cells, a result only partially explained by a higher rate of paricalcitol chemical degradation. 111 Moreover, a recent preclinical study by Davies et al. demonstrated a favorable bone metabolism effect with paricalcitol therapy in an animal model of adynamic bone disease. 112 In comparison to calcitriol, paricalcitol was found to increase distal femur trabecular bone volume, demonstrating anabolic growth in a low-bone turnover model. 112 Together, these studies suggest that paricalcitol therapy results in less bone demineralization while maintaining similar or greater bone growth, as evidenced by collagen synthesis.

Cinacalcet
Calcimimetics are novel agents that increase the sensitivity of the CaR in the parathyroid gland. 113 Binding to the transmembrane domain of the CaR, type II calcimimetic agents induce a conformation change in the CaR that lowers the activation threshold for serum calcium. 114 Thus, these drugs suppress PTH secretion at calcium levels below the normal physiological concentration. 115 Cinacalcet HCl (Sensipar), a type II calcimimetic agent, is the only FDA-approved calcimimetic. 114 Cinacalcet is available as a oncedaily oral formulation for the treatment of SHPT in adult CKD stage 5 patients on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma. 114 Proven safe and effective in clinical trials, cinacalcet has been shown to substantially suppress PTH levels without concomitant elevations in calcium, phosphorus, or Ca x P. A randomized controlled trial undertaken by Block et al. evaluated cinacalcet therapy over a 26-week study period, finding a 43% reduction in mean PTH levels among recipients. 116 In a short 18-week RCT, Lindberg et al. found an average decrease of 26% in PTH level in cinacalcet patients, compared with a 22% increase in the placebo group. Serum calcium levels decreased by 4.7% and Ca x P decreased by 11.9% in cinacalcet recipients. 117 These results were later corroborated in a multicenter RCT performed by Lindberg et al. over a 26-week study period. 118 The investigators found cinacalcet therapy was effective in reducing PTH levels ≥30% from baseline versus control (65% of patients vs. 13% of patients) and in reaching target PTH levels ≤300 pg/mL versus control (46% of patients vs. 9% of controls).
In a multicenter RCT to evaluate higher dosages, Quarles et al. found a maximum reduction of 60% in PTH level from baseline accompanied by a 4.6% decrease in serum calcium. 119 Serum phosphorus levels, however, were comparable between cinacalcet and placebo groups. The most common adverse effects as reported by the package insert include nausea (31%) and vomiting (27%) in patients with baseline calcium levels below 8.4 mg/dL. 120 While clinical trials have reported significant improvements in Ca x P, PTH, and calcium and phosphorus levels, data demonstrating the impact of cinacalcet on all-cause mortality, bone histomorphometry, fracture rate, cardiovascular event rate, and other hard patient-based outcomes is lacking. 106,121 Furthermore, all studies except one have reported treatment outcomes only up to 6 months, seriously limiting the data on long-term effects of treatment. 21 While showing promise, there is a lack of comparative data between cinacalcet and vitamin D therapies, highlighting the need for future head-to-head trials.

Parathyroidectomy
Surgical parathyroidectomy is the oldest treatment option for hyperparathyroidism and is reserved for patients refractory to other therapies. Surgery carries risks, including anesthetic risks, preoperative and postoperative complications, and, importantly, injury to the recurrent laryngeal nerve. Furthermore, because of the varied number of parathyroid glands (4 is normal, but the range is 3-7), failure to remove or locate all the glands may require additional surgery. Even total parathyroidectomy has proven ineffectual in certain patients, as reported by Stracke et al., possibly because of ectopic parathyroid tissue. 122 Removal of too much parathyroid gland, however, can result in permanent hypoparathyroidism and severe hypocalcemia, requiring patients to be prescribed daily calcium supplementation. 123,124 Thus, although parathyroidectomy is often necessary in patients with severe recalcitrant SHPT, the surgical option remains a suboptimal treatment option for CKD patients.

Direct Costs of Treating Secondary Hyperparathyroidism
In order to better understand the economic burden associated with CKD, Smith et al. recently performed a large observational study (n = 13,796 predialysis CKD patients) investigating direct medical costs and resource utilization in the predialysis population. 125 Dividing the control group into 2 cohorts, 1 presenting with several CKD-related comorbidities (n = 12,459) and 1 without any comorbidities (n = 1,337), the authors were able to separate the per-patient-per-year costs of CKD from the CKD-related comorbidities within the case population. They determined that the cost to treat CKD-related comorbidities was almost twice that of treating CKD alone, $14,000 vs. $8,000, respectively. Of perhaps greater concern was the finding that the cumulative cost of CKD plus comorbidities was greater than their simple sum, $26,000 vs. $22,000, respectively. Taken together, these findings underscore the importance of actively treating the etiology of the comorbidities and not passively waiting for the comorbidities to develop.
Unfortunately, despite such findings, SHPT remains consistently underrecognized, underdiagnosed, and undertreated by clinicians. This problem is evidenced in the lack of large-cohort epidemiological studies of SHPT among predialysis patients, making thorough determinations of prevalence challenging. Two studies, to date, have attempted to estimate the prevalence of SHPT in the CKD population. The first estimate made by De Boer et al. found that up to 24% of CKD stages 3-4 patients suffered from mild-tomoderate SHPT, compared with the 19% to 31% of ESRD patients who presented with moderate-to-severe SHPT. 126,36 The second study by Levin et al. found that 56% of predialysis patients with an eGFR <60 ml/min/1.73 m 2 (CKD stages 3-5) had elevated PTH levels. 127 While these 2 studies found significantly different frequencies of hyperparathyroidism, these differences can be attributed to the reference values used for a cutoff point. Abnormal PTH levels were considered to be >195 pg/ml by De Boer et al., whereas Levin et al. considered >65 pg/ml to be abnormal. Despite their significantly different findings, these 2 studies reinforce the fact that abnormal PTH levels are prevalent among the CKD population. The K/DOQI guidelines define target PTH values according to CKD stage: stage 3, 35 to 70 pmol/L; stage 4, 70 to 110 pmol/L; and stage 5, 150 to 300 pmol/L. Data regarding CKD stage-related estimates of the percentage of patients compliant with PTH targets are lacking.
According to the K/DOQI guidelines, the prevalence of stages 3, 4, and 5 CKD in the United States is 7.6, 0.4, and 0.3 million, respectively. 1 Therefore, using the SHPT prevalence findings from De Boer et al. and Levin et al., respectively, we can assume that between 2.0 million and 4.7 million individuals with CKD have elevated PTH levels and therefore would be candidates for the above-mentioned treatment options. These findings, together with the findings from Smith et al., 125 show that the cost to treat these individuals and the comorbidities that are predicted to develop are in the range of $52 billion to $122 billion. However, if the comorbidities could be prevented or significantly delayed, the costs would range from $16 billion to $37 billion, a cost savings of between $36 billion and $85 billion.

■■ Conclusions
There is an increasing body of evidence, largely observational, that shows that elevated PTH levels cause deleterious physiological effects across a variety of organ systems, including the cardiovascular manifestation of LVH, a common cause of morbidity and mortality in CKD. Mild-to-moderate LVH affects 87% of predialysis patients and occurs with severe pathophysiology in 52% of dialysis patients. 64,65 In the skeletal system, osteodystrophy occurs with a prevalence of more than 90% in chronic hemodialysis patients as a consequence of progressive mineral depletion from bone, resulting in fractures and other complications. 128 Medical management of PTH and mineral imbalances in CKD focuses on controlling SHPT with vitamin D therapy. New vitamin D analogs have the benefit of reducing PTH levels with fewer hyperphosphatemic and hypercalcemic episodes, a problem often associated with calcitriol therapy. In addition, a paucity of comparative clinical data for doxercalciferol indicates the superiority of paricalcitol but supports doxercalciferol as a therapeutic alternative for patients refractory to other vitamin D therapies. 129 Alternatively, calcimimetics represent another avenue of medical management of SHPT but their value (on hard endpoint outcomes versus biochemical outcomes) has not been established in clinical trials. The therapeutic landscape at present relies in large part on observational data, motivating future controlled trials to clarify several questions that remain to be answered in a convincing manner. In particular, studies should focus on determining optimal PTH levels, particularly regarding bone disease, evaluating proper staging to initiate treatment, collecting important prevalence data, and calculating costs for the treatment of SHPT.
The K/DOQI guidelines established by the National Kidney Foundation have altered the treatment paradigm of CKD, expanding clinical focus past dialysis to view the disease as a progressive illness capable of maintenance. 130 Recent studies have reinforced this perspective, recognizing that the bulk of the morbidity, mortality, and economic burden of CKD lies in the comorbidities that accompany the development of SHPT very early in CKD. 8,9,41,44,57,74,75,76,126

DISCLOSURES
No outside funding supported this research. Author Melanie S. Joy discloses that she has served on the advisory boards and/or as a consultant for Abbott Laboratories, Amgen, Inc., and Shire. She also received funding to cover the expenses of conducting phase 2 and 3 studies for drugs related to the subject of this article-cinacalcet from Amgen, Inc., and lanthanum carbonate from Shire. Authors Paul C. Karagiannis and Fred W. Peyerl disclose that they have served as consultants for Abbott Laboratories. Joy served as principal author of the study. Study concept and design were contributed primarily by Joy, with input from the coauthors. Data collection and data interpretation were the work of all authors. Writing of the manuscript was the work of all authors; its revision was the work of Peyerl and Karagiannis, with input from Joy.